title: Distribution and diversity of the haemoglobin-haptoglobin iron-acquisition systems in pathogenic and non-pathogenic Neisseria.
abstract: A new generation of vaccines containing multiple protein components that aim to provide broad protection against serogroup B meningococci has been developed. One candidate, 4CMenB (4 Component MenB), has been approved by the European Medicines Agency, but is predicted to provide at most 70-80 % strain coverage; hence there is a need for second-generation vaccines that achieve higher levels of coverage. Prior knowledge of the diversity of potential protein vaccine components is a key step in vaccine design. A number of iron import systems have been targeted in meningococcal vaccine development, including the HmbR and HpuAB outer-membrane proteins, which mediate the utilization of haemoglobin or haemoglobin-haptoglobin complexes as iron sources. While the genetic diversity of HmbR has been described, little is known of the diversity of HpuAB. Using whole genome sequences deposited in a Bacterial Isolate Genome Sequence Database (BIGSDB), the prevalence and diversity of HpuAB among Neisseria were investigated. HpuAB was widely present in a range of Neisseria species whereas HmbR was mainly limited to the pathogenic species Neisseria meningitidis and Neisseria gonorrhoeae. Patterns of sequence variation in sequences from HpuAB proteins were suggestive of recombination and diversifying selection consistent with strong immune selection. HpuAB was subject to repeat-mediated phase variation in pathogenic Neisseria and the closely related non-pathogenic Neisseria species Neisseria lactamica and Neisseria polysaccharea but not in the majority of other commensal Neisseria species. These findings are consistent with HpuAB being subject to frequent genetic transfer potentially limiting the efficacy of this receptor as a vaccine candidate.
authors.affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3SY, UK.
authors.forename: Odile B
authors.initials: OB
authors.lastname: Harrison
authors.affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3SY, UK.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Bennett
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Derrick
authors.affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3SY, UK.
authors.forename: Martin C J
authors.initials: MCJ
authors.lastname: Maiden
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Bayliss
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D006242:Haptoglobins / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008969:Molecular Sequence Data; D009343:Neisseria / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D016870:Neisseriaceae Infections / Q000382:microbiology; D010802:Phylogeny; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D006242:Haptoglobins; D006454:Hemoglobins; C094109:HmbR protein, Neisseria meningitidis; C445303:HpuA protein, Neisseria; C105625:HpuB protein, Neisseria; D011956:Receptors, Cell Surface; D007501:Iron